Certain amino hydrocarbon sulfones and process of preparation



Patented Nov. 18, 1952 UNITED STATES CERTAIN AMINO HYDROCARBON SULFONESAND PROCESS OF PREPARATION Sydney Archer and Chester M. Suter, AlbanyCounty, and Benjamin F. Tullar, Rensselaer, N. Y., assignors to SterlingDrug Inc., Wilmington, Del., a corporation of Delaware No Drawing.Application May 18, 1948, Serial No. 27,826

22 Claims. 1 This invention relates to basic sulfones and to methods ofpreparing the same.

More particularly, the basic sulfones of this invention are those havingthe formula where B is a lower aliphatic tertiary-amino group, X is alower alkylene group, Ar and Ar are aryl groups, and R is a lowerhydrocarbon radical. These basic sulfones are of interest because oftheir pharmaceutical Value, especially because of their analgesicactivity.

In the above formulas the lower aliphatic tertiary-amino group,designated as B, comprehends lower dialkylamino groups illustrated byexamples such as dimethylamino, diethylamino, din-butylamino,ethylmethylamino, and the like; and lower saturated N-heterocyclicgroups illustrated by examples such as 1-piperidyl, 2-methyll-piperidyl,l-pyrrolidyl, l-morpholinyl, and the like. In other words, BH designatesa lower aliphatic secondary-amine as illustrated by diethylamine,di-nbutylamine, morpholine, 2,6- climethylpiperidine, and the like. Thelower alkylene group, designated as X, preferably contains 2-6 carbonatoms and includes such examples as -CH2CH2, -CH2CH2CH2,

CH3$H(C2H5), --CHzCH2( 3H(CH3) CH2CH2CH2CH2CHr-, --CH2C}IZCHZ(IDH(CH3)and the like. Ar and Ar, which can be the same or different, are eacharyl radicals of preferably 6-10 carbon atoms. The aryl radicals can besubstituted by such groups as hydroxy; alkoXyl such as methoxyl,ethoxyl, etc. dialkylamino such as dimethylamino; halogen, such aschloro, bromo, or ionic; and lower alkyl such as methyl, ethyl, butyl,etc.; and other groups which the chemist appreciates will be unaffectedby the reaction conditions used in the preparation of the basic sulfonesof our invention. Moreover, Ar and Ar can be linked in ortho positions,either directly to form the fluorene ring, or through such atoms ascarbon, oxygen, sulfur, or nitrogen to form respectively the rings of9,10-dihydroanthracene, xanthene, thioxanthene, or acridan. Thehydrocarbon radical, designated by R in the formula above, is preferablya lower hydrocarbon group of 1-8 carbon atoms including alkyl groups250-293AJ Y 2 such methyl, ethyl, n-propyl, n-butyl, Z-butyl, tamyl,n-octyl, and the like; and cycloalkyl groups such as cyclohexyl,cyclopentyl, cyclopropyl, 2- methylcyclohexyl, and the like. Specificexamples of compounds comprehended by our invention include thefollowing:

(1) 3 diethylamino 1,1 diphenylpropyl npropyl sulfone,

CsHs (C2H5)ZNCH2CHZ( JSO2 CH2CH2OH3 CaHa (2). 3 dimethylamino 2 methyl1,1 diphenylpropyl n-butyl sulfone,

CaHs

(CH3)gNCHzCH-CSOzOH2OH CH CHa (3). 4 (1 piperidyl) 1 (3-ethoxyphenyl)l-phenylbutyl ethyl sulfone,

CHzCH2 OCaHs (4). 3 (2 methyl 1 piperidyl) 1,1 bis-(1methoxyphenyl)vpr'opyl cyclopentyl sulfone,

CHr-CH CHr-CHz (5). 5 dimethylamino 1,1 diphenylpentyl methyl sulfone,

CnHs oHmNoHzo112oH2oHzt-soR-oH3 luHa (6). 9 (2 (4 morpholinyl) ethyl) 9fluorenyl methyl sulfone,

CHzCHz-N O CHz-CH:

('7). 10 (2 dimethylamino l propyD-IO- thioxanthenyl ethyl sulfone,

The compounds of our invention can be prepared by different methods. Onemethod is represented by the following series of reactions:

The designations Ar, Ar, R, B, and X have the same meanings ashereinbefore given. In step I a diarylmethanethiol (A) is treated with ahydrocarbon halide, R-halogen, in the presence of a strong base, such asan alkali alkoxide, an alkali triphenylmethyl, sodium hydride, or thelike, to form a sulfide, C. This sulfide is oxidized in step II (bymethods later to be illustrated) to yield the corresponding sulfone, D,which, in step III, is condensed witha tertiary-aminoalkyl halide,BX-halogen, in the presence of a strongly basic condensing agent, suchas sodium amide, sodium hydride, phenyllithium, or the like, to yieldthe basic sulfone, E. Illustrative of this method is the preparation of'3-diethylamino-1,l-diphenylpropyl ethyl sulfone by the following steps:I. Diphenylmethanethiol, in ethanolic solution, is treated with ethyliodide in the presence of sodium ethoxide to give benzohydryl ethylsulfide; II. This sulfide is oxidized with hydrogen peroxide to producethe corresponding sulfone; III. The resulting sulfone is condensed with2-diethylaminoethyl chloride in the presence of sodium amide to yield3-diethylamino-1,1-diphenylpropyl ethyl sulfone having the formula C6115o2H5)2NoH2oH2( Jsz-o2m CHHE Examples of the type of mercaptan designatedhereinabove as a diarylmethanethiol, and represented by A above, areknown; thus diphenylmethanethiol was prepared by Staudinger and Siegwart(Ber. 49, 1918 (1916)) by the action of hydrogen sulfide ondiphenyldiazomethane. We

have found that this thiol can be prepared by a more convenient methodinvolving treating benzohydryl chloride with thiourea to form thecorresponding thiuronium chloride which in turn, is readily hydrolyzedto diphenylmethanethiol. We have found that the thiuronium salt can beisolated in a pure state, but We prefer to hydrolyze the crude saltdirectly according to the usual method (Organic Synthesis, 21, 36(1941)). In this way we are able to obtain a fairly constant boiling,pale blue oil which according to iodometric assay is benzohydrylmercaptan of about 85% purity. The contaminants are probably some of thecorresponding sulfide and diphenylmethane, the latter possibly beingformed by disproportionation during the hydrolysis. By the same methodof analysis the undistilled thiol is shown to be about 75% pure. Thecompound in either state of purity is suitable as an intermediate incarrying out our invention, Similarly, using other diarylmethyl halideswe are able to obtain the corresponding mercaptans which are suitablefor further use even in impure form (see step I above); for example,using 9-chlorofiuorene, 9-fiuorenethiol is obtained.

In step II above, the oxidation of the sulfide, C, to the correspondingsulfone, D, is readily accomplished by using oxidizing agents wellsuited for this purpose, such as hydrogen peroxide, chromic anhydride(CIOs), potassium permanganate, etc. (see Organic Chemistry of Sulfur bySuter, John Wiley 8: Sons, Inc., Chapman & Hall, Ltd., London, 1944, pp.660-67).

In practicing step III we prefer to use sodium amide as the condensingagent because of its availability and low cost. Toluene is preferred asthe reaction medium, however other solvents, in view of what has beensaid, will suggest themselves to those'skilled in the art. Such solventsinclude benzene, xylene or other suitably volatile liquid inerthydrocarbons. Usually the mildly exothermic reaction starts at about C.and is completed by refluxing the reaction mixture for a few hours. Thetertiary-aminoalkyl'halide, designated as BY-halogen above, can be usedas such or in the form of an acid-addition salt, e. g. thehydrochloride, sulfate, etc. When a salt is used an extra equivalent ofsodium amide is employed. After the excess condensin agent has beendestroyed, e. g., with ethanol, the basic sulfone is extracted from thereaction mixture with dilute hydrochloric acid. In many instances thereaction product separates in crystalline form after treatment of theacidic extract with dilute base such as aqueous sodium hydroxidesolution. If the basic sulfone cannot readily be obtained solid, it isusually possible to purify it by conversion to the hydrochloride or someother suitable salt.

In the condensation of a tertiary-aminoalkyl halide, BX-halogen, with adiarylmethyl hydrocarbon sulfone, AICH(Ar')SO2R, said condensation beingdesignated as step III above, there is the theoretical possibility oftwo different types of condensation products being formed, depending nwhether the entering tertiary aminoalkyl group replaces the diarylmethylhydrogen or an alpha-hydrogen of the hydrocarbon group. These twotheoretical possibilities are represented by the following formulas BX-C(Ar) (Ar')--'SOz-R Type I and A1CH(A1")--SO2--R'XB Type 'II where B, X,Ar, Ar'and R have the meanings hereinabove specified and R is R. minusan alpha-hydrogen atom. We have found two types of evidence thatstrongly indicate the above condensation results in the formation of thebasic sulfones of Type I.

One type of evidence involves the synthesis of a, compound of Type II(Compounds of this type are disclosed and claimed in the copendingArcher and Suter application Serial No. 150,556, filed March 18, 1950)and the comparison of the properties of this basic sulfone with those ofthe basic sulfone prepared by condensing a diarylmethyl hydrocarbonsulfone with a tertiary-aminoalkyl halide. We have condensed methylbenzohydryl sulfone with 2- (l-piperidyl) ethyl chloride and thus wehave obtained a basic sulfone of MP. 122-123 C. This compound couldconceivably be either Y or Z.

GEE-CH2 C6115 E2 N-CHzCH2C-SO2CH3 CHE-C 2 01511 Y CHz-CHe(CsH5)2CH-SOQ-CH CH CH N CH CHz -Cz Z It proves not to be Z, andtherefore must be Y, by the following argument. We prepared benzohydryl3-(l-piperidyDpropyl sulfone, Z, of known structure according to thefollowing equations:

oenplonsrr Br(CHz)aCl The last step is carried out by treatin theintermediate benzohydryl 3-chloropropyl sulfone with piperidine. Thebasic sulfone thus obtained melts at 120-121 C. Despite the proximity ofmelting points of the two basic sulfones, admixture of the two specimensresults in a large melting point depression. Therefore the productobtained by the treatment of benzohydryl methyl sulfone with2-(l-piperidyl) ethyl chloride must must be Y, or 3-(1-piperidyl)-1,1-diphenylpropyl methyl sulfone.

Another type of evidence that compounds of Type I above are formed bythe condensation of a tertiary-aminoalkyl halide with a diarylmethylhydrocarbon sulfone is afforded by another method which is fullydescribed below in Example 3C. Therein is shown that a basic sulfoneobtained by said condensation when degraded results in the formation ofa tertiaryamine which must be formed from a basic sulfone of Type I andnot from one of Type II.

Another mode of synthesis of our basic sulfones is afiorded by themethod presented in the following equations:

CHOH R-SOzH T 6. the synthesis of 4-dimethylamino-L1-bis (4dimethylaminophenyDbutyl ethyl sulfone. This can be obtained by treatingbis(4-dimethylaminophenyl) caribinol with ethanesulfinic acid in thepresence of dilute acid, e. g. hydrochloric, to givebis(4-dimethylaminophenyl) methyl ethyl sulfone (step IV) and condensingthis sulfone (step III) with 3-dimethylaminopropyl chloride. Theresulting basic sulfone has the formula The intermediate sulfonesdesignated as D also can be prepared by other means; such as, bytreating a diarylmethyl halide, having the formula Ar(Ar')CI-I-halogen,with a salt of a hydrocarbon-sulfinic acid, RSOzI-I, or by treating adiarylmethyl halide, Ar(Ar)CI-I-halogen, with a hydrocarbon-thiol,RSI-I, to give the sulfide, Ar(Ar)CH-SR, which is then oxidized to thecorresponding sulfone. Illustrative of the former method is thepreparation of bis(4-methoxyphenyDmethyl n-propyl sulfone from bis(4-methoXyphenyDmethyl chloride and sodium r n-propanesulfinate.

It is often convenient to isolate and use the basic sulfones of ourinvention as the watersoluble hydrochloric acid addition salts. It is,of course, understood that other water-soluble salts, such as thosederived from other nontoxic inorganic acids, including hydrobromic acid,sulfuric acid, phosphoric acid, sulfamic acid, and the like, andnon-toxic organic acids, including tartaric acid, citric acid, succinicacid, acetic acid, benzoic acid, oleic acid, and the like, will servethe same purpose and are within the scope of our invention.

Also within the scope of our invention are the quaternary salts of ourbasic sulfones derived from union of the basic sulfones with esters ofinorganic acids, e. g. methyl iodide, ethyl bromide, benzyl chloride,and the like.

The following examples will further illustrate specific embodiments ofthe invention.

EXAMPLE 1 A. DiphenyZmethanethioZ.A solution of 254 g. of benzohydrylchloride, and 97.5 g. of thiourea in 510 ml. of alcohol is refluxed fortwo hours. A solution of '76 g. of sodium hydroxide in 600 ml. of wateris then added and refluxing continued for two hours more during whichtime a pink oil separates. The mixture is cooled and the supernatantaqueous layer decanted. The aqueous solution is treated with dilutesulfuric acid (10 ml. of concentrated acid in 100 ml. ofwater) andextracted with ether. The ether extract is combined with the pink Oil,and the resulting solution is dried and distilled to give 209 g. of apale blue liquid boiling mainly at 135 C. at 1.5 mm. and mainlycomprising diphenylmethanethiol (benzohydryl mercaptan).

The above procedure can be carried out using benzene rather than etherfor the extraction. The oil that remains after removal of the benzene bydistillation is about 75% diphenylmethanethiol according to iodimetricassay. A portion is distilled and the fraction distilling at 122-5 C. at0.8 mm. analyzes for diphenylmethanethiol of about 83% purity. Eitherthe distilled or undistilled product is satisfactory for further use asdescribed below (see Example l-B).

The above procedure also can be carried out substituting an equivalentamount of benzohydryl bromide for the corresponding chloride.

The isothiuronium salt is obtained when a so- .lution of 365 g. ofbenzohydryl chloride and 137 g.

of thiourea in 710 ml. of ethanol is refluxed for 'two hours and thencooled. About 440 g. (88%) of a White crystalline solid,benzohydrylisothiuronium chloride, which after crystallization fromethanol melts at 196 0., is obtained.

B. Beneohydryl ethyl suljone-To a solution of sodium ethylate preparedfrom 3.5 g. of sodium and 200 ml. of absolute ethanol are added g. ofdiphenylmethanethiol of 75% purity (see Example l-A) and 22.4 g. ofethyl iodide. The solution is stirred under reflux for three hours andthen poured into ice water. The oil is taken up into ether, the ethersolution dried over anhydrous sodium sulfate, and the ether removed invacuo on the steam bath. To insure removal of excess ethyl iodide,ethanol is added to the crude concentrate and the solution concentratedagain. The residue is dissolved in 115 ml. of acetic acid, and 115 ml.of 30% hydrogen peroxide solution is added dropwise with stirring over aperiod of about thirty minutes while maintaining. the temperature at80-98 C. The resulting mixture is stirred for an additional thirtyminutes and then poured onto ice. The solid that separates is filteredand recrystallized from dilute ethanol to yield about 25 g. ofbenzohydryl ethyl sulfone, M. P. l-6 C.

C. 3 (1 piperidyl) -1,1- diphenylpropyl ethyl sulfone. A mixture of 39g. of benzohydryl ethyl sulfone, 22.2 g. of 2-(1-piperidyl)ethylchloride, and 6.0 g. of sodium amide in 150 ml. of toluene is heated ona steam bath. At 50 C. a spontaneous reaction occurs, the temperaturerising to-70 C. When the evolution of ammonia slackens, the mixture isheated at 90 C. for four hours. The suspension is cooled and a few ml.of ethanol is added to destroy any unreacted sodium amide. The mixtureis washed with water and then extracted with two 100 ml. portions of 10%hydrochloric acid. The combined acidic extracts are made alkaline with 3N sodium hydroxide solution and the supernatant liquid is then decantedfrom the gun, which solidifies when triturated with ethanol. After tworecrystallizations from ethanol there is obtained 23.0 g. of3-(1-piperidyl)-1,1-diphenylpropyl ethyl sulfone, M. P. 1l'7.5-l19 C.(corn).

EXAMPLE 2 A. Benzohydryl methyl sulfone.--A solution of 60 g. ofdiphenylmethanethiol (of about 83% purity), 6.9 g. of sodium, and 18.9ml. of methyl iodide in 300 ml. of ethanol is stirred under re flux forthree hours. The ethanol is removed by distillation in vacuo and theresidue poured into water. The oil is taken up in ether, the etherextract dried over anhydrous sodium sulfate, and the ether removed bydistillation. The residue is distilled in vacuo yielding the mainfraction of 31 g., b. p. 135 C. at 1.5 mm. To a stirred solution of 28.3g. of this benzohydryl methyl sulfide in 78 ml. of acetic acid held at80 C. is added dropwise '78 ml. of 30% hydrogen peroxide solution over aperiod of about thirty minutes. After being stirred an additional thirtyminutes, the reaction mixture is poured into water, and the precipitatedsolid is collected by filtration and recrystallized from dilute ethanolyielding about 29. g. of benzohydrylmethyl sulfone, M. P. 127-8.5 C.

B. 3 -(1-piperidyl)1,1- diphenylpropyl methyl sulfone.This preparationis carried out according to the directions given in Example l-C, butusing 36.9 g. of benzohydryl methyl sulfone, 6.0 g. of sodium amide, and22.2 g. of 2-(1-piperidyl) ethyl chloride in 150 m1. of toluene at C.for four hours. The product, 3-(1-piperidyl) -1,1- diphenylpropyl methylsulfone, after recrystallization of 36 g. of crude crystalline sulfone,melts at 122.6-123.6 C. (corn) When a sample of this basic sulfone isadmixed with a sample of benzohydryl 3-(1-piperidyl)propyl sulfone, M.P. 119-120" C. (disclosed and claimed in the copending Archer and Suterapplication Serial No. 150,556, filed March 18, 1950) a clear meltresults before the temperature reaches C., thus establishing thenon-identity of the two samples.

If the above preparation is run, but substituting3-dimethylamino-2-propyl chloride for 2-(1- piperidyl) ethyl chloride,there is obtained, after two recrystallizations from ethanol,3-dimethylamino-1,1-diphenylbutyl methyl sulfone, M. P. 148.6- C.(C0111).

EXAMPLE 3 A. 3-dimethyZamz'no-L1-diphenylbutyl ethyl sulfone.When amixture of 39 g. of benzohydryl ethyl sulfone, 6.3 g. of sodium amide,and 20 g. of 3-dimethylamino-2-propyl chloride is heated for four hoursand then worked up according to the directions given in Example 1-C, thehydrochloride of the desired amino sulfone (about 27 g.) separates fromthe acidic extract directly. Recrystallization from ethanol-ethylacetate yields the purified product, 3-dimethyl'amino- 1,1-diphenylbutyl ethyl sulfone hydrochloride, M. P. 205206.5 C. (corn).The filtrate from the hydrochloride is made basic, and the base thatseparates is converted to the hydrochloride as above to give anadditional 8 g. of product.

The preparation described in the previous paragraph can also be runusing sodium hydride as the basic condensing agent. The followingprocedure is exemplary: A mixture of 332 g. of ethyl benzohydryl sulfoneand 38.3 g. of sodium hydride in 1280 ml. of dry benzene is heated withstirring for twenty-six hours. Then 180 g. of 3-dimethylamino-2propylchloride is added dropwise over a period of one hour. After heating foran additional five hours, the mixture is cooled and 30 ml. of ethanoladded to destroy the excess sodium hydride. The suspension is Washedwith two 500 ml. portions of water and then shaken with 600 ml. of 2.5 Nhydrochloric acid. A part of the hydrochloride of the basic productseparates immediately. The benzene layer is decanted and Washed with 200ml. of 10% hydrochloric acid. The acid fractions are combined and cooledto C. The salt, 3-dimethylamino-1,1-diphenylbutyl ethyl sulfonehydrochloride, is collected and washed with 100 ml. of 6 N hydrochloricacid. The combined acid filtrates yield 19 g. of crude S-dirnethylamino-1,1-diphenylbuty1 ethyl sulfone after being made alkaline with sodiumhydroxide solution. The main portion of the hydrochloride salt isdissolved in 2 liters of water and 600 ml. of ethanol, filtered and madebasic with 35% sodium hydroxide solution. The suspension is cooled inice with Stirring for one half hour and then filtered. The base iscollected and combined with the crude crop obtained above, the totalyield being 236 g. or 54% of theory. On recrystallization from ethanolthere is obtained 196 g. (45%) of 3-dimethylamino-l,l-diphenylbutylethyl sulfone (this material is suitable for use in the resolution asdescribed in Example 3B). An analytical sample is obtained after twomore crystallizations from ethanol, M. P. 150.5-151.8 C. (corr.).

Concentration of the benzene fraction gives a recovery of 97 g. (29%) ofbenzohydryl ethyl sulfone which has not reacted.

7 The condensation using sodium hydride just described can be runsubstituting toluene for benzene. The mixture of benzohydryl ethyl sulfone, dry toluene and sodium hydride is kept at 110 C. until theevolution of hydrogen subsides (about three hours), and then the3-dimethylamino-2-propyl chloride is added and the preparation continuedas above.

B. Resolution of 3-dimethylamino-1,1diphenylbutyl ethyl suZfone.Thepreparation described in Example 3A is racemic. It can be resolved intothe two optically active forms by taking advantage of the difierence insolubility of the diastereoisomeric deXtro-bitartrate in aqueousacetone. A levorotatory salt separates first; this yields a crystallinebase which is dextrorotatory in acetone. A two per cent solution of thebase in U. S. P. ethanol does not give any measurable rotation. On theother hand, the hydrochloride is levorotatory in aqueous solution. Forconvenience, the sulfone which yields levorotatory salts is designatedas the levo-base. The isomeric sulfone is obtained from the filtrates ofthe levo-bitartrate after treatment with ammonia followed by dilution.It is of interest to note that the active bases and hydrochlorides meltlower than the corresponding racemic substances.

Levo-3-dimethyZamino-L1diphenylbutyl ethyl sulfone and salts thereof-Asolution of 196 g. of dl-3-dimethylarnino-l,l-diphenylbutyl ethylsulfone (as prepared in Example 3A) in 3 liters of acetone is added to asolution of 88 g. of dextro-tartaric acid in an equal volume of waterand then cooled to 5 C. for 24 hours. The crystals that separate arewashed with 200 m1. of cold 50% acetone and then with pure acetone.After drying at 50 C. there is obtained 119 g. (79%) oflevo-3dimethylamino-1,1-diphenylbutyl ethyl sulfone dextro-bitartrate,M. P. 169-1'71 C., as a di'hydrate.

The filtrates are made basic with '75 ml. of concentrated ammoniumhydroxide, stirred at 10 C. for one-half hour and then filtered. Thesolid, which is the racemic base, amounts to 50 g. It is resolved asabove and an additional 21 g. of the levo-sulfone deXtro-bitartrate isobtained. The recovery of racemic base is 22 g. A second crop yields anadditional 6 g. of 1eV0 salt. The combined fractions of practically purelevosulfone deXtro-bitartrate weighs 1 16 g. or 96% .of the theoretical.It is dissolved in 1200 ,ml. of

10 50% acetone containing 3.0 g. of dextro-tartaric acid and cooled. Thesolid is collected and dried at 50 C. to give 136 g. of purelevo-sulfone dextro-bitartrate dihydrate which is converted to theanhydrous form by drying at C. for fifteen hours. The anhydrouslevo-sulfone dextro-bitartrate melts at I'll-172.5 C. (corr.).

Addition of ammonia to the filtrate from the above crystallizationcauses 4.7 g. of dl-base, M. P. 145-148" C., to separate.

The levo-sulfone base is prepared by dissolving 191 g. of the purelevo-sulfone dextro-bitartrate in 1800 ml. of 50% acetone and making thesolution alkaline with concentrated ammonium hydroxide. After cooling to5 C. the solid is collected and dried; wt. 120 g. It is recrystallizedfrom ethanol, yielding levo-3- dimethylamino-1,1diphenylbutyl ethylsulfone, M. P. -1108 C. (corr.).

The levo-hydrochloride is prepared by dissolving at 80 C. g. of thelevo-sulfone base in 250 ml. of water containing 35 ml. of concentratedhydrochloric acid and cooling to 5 C. The salt is filtered and dried toconstant weight at 70 (3.; wt. 118 g. It is recrystallized from 700 ml.of acetone to give 100 g. of pure levo-3-dimethylamino-1,1-diphenylbutylethyl sulfone hydrochloride, M. P. 196-197 C. (corr.).

Dextro 3 dimethyZamino-LZdiphenylbutyl ethyl sulfone and saltsthereof.The combined ammoniacal filtrates from which all the racemicbase has been removed are diluted to 16 liters and allowed to cool aftercrystallization starts. The solid that separates weighs 60 g. and meltsat 106-110 C. After recrystallization from 14.0 ml. of 95% ethanol thepure dextro-3-dimethylamino-1,1-diphenylbutyl ethyl sulfone, M. P.1l0-110.6 C. (corr.) is obtained.

Twenty grams of the dextro-sulfone base is dissolved in 40 ml. of watercontaining 6 ml. of hydrochloric acid and cooled. The dextro-sulfonehydrochloride is collected and dried; wt. 21 g. After recrystallizationfrom acetone the pure dextro-3dirnethylamino-1,1-diphenylbutyl ethylsulfone hydrochloride amounts to 15 g., M. P. 196.8-198 C. (corr.)

The dextro-sulfone dextro-bitartrate is prepared in 50% acetone fromequimolar quantities of the dextro-sulione base and dextro-tartaricacid. From 5.3 g. of base there is obtained 4.5 g. of puredextro-3dimethylamino-1,1-diphenylbutyl ethyl sulione dextro-bitartrate,M. P. 166-169 C. (corr.).

The properties of all the above optically active compounds are listed inTable 1.

1 Five percent solution of base in water plus equivalent quantity ofcone. E01.

C. Structure proof of basic suZfone of Example 3A.-In the condensationof benzohydryl ethyl sulfone with 3-dimethylarnino-2-propyl chloride 11two isomeric products are possible depending on whether or notrearrangement of the entering alkamine group occurs. These two possibleisomers are 3 dimethylamino 1,1 diphenylbutyl ethyl sulfone (I) and3-dimethylamino-2-methyl- 1,1-diphenylpropyl ethyl sulfone (II), havingthe formulas:

I CeHt (CHs)2NCHCE2.( -SO C II Ha H5 While it is possible that both ,ofthese isomers may be formed in the reaction, we have so far onlyobtained one compound in a crystalline form from the reaction mixture.As shown in the following presentation the compound isolated has thestructure I, and arises from a rearrangement during the condensation.

The structure proof can be represented by the following two equations:

Previous workers have prepared the nitrile III by other methods andproved its structure (Schutz et al., JACS 69, 188, 2454 (1947) Easton etal., ibid. 69, 2941 (1947)). When it is heated with excess sodium amidein boiling toluene, the CN group is replaced by hydrogen to give thebase IV (see below for experimental data), which forms a nicelycrystalline hydrochloride which melts at 156-158 C. afterrecrystallization from acetone. When the sulfone, I, is refluxed inethanol with Raney nickel catalyst, hydrogenolysis occurs at thecarbon-sulfur bond. A high boiling basic oil is obtained which yields ahydrochloride identical with the one prepared from III. Since neitherstep in the degradations involves the side chain, the evidence isconclusive that the crystalline basic sulfone isolated from the reactionmixture of Example 3A (reaction of benzohydryl ethyl sulfone with3-dimethylamino-2- propyl chloride) is 3dimethylamino-l,1-diphenylbutylethyl sulfone and has the structure of formula I.

Cleavage of 4-dimethylamino-2,2-diphenylbu1 tane-3-mtriZe.-A mixture of27.8 g. of 4-dimethylamino-.2,2ediphenylbutanenitrile, 15.6 g. of sodiumamide, and 150 ml. of dry toluene is refluxed with stirring for twelvehours. Excess sodium amide destroyed with ethanol and the mixture thenpoured into water. The toluene layer is shaken with dilute hydrochloricacid and the acid extract then made basic with dilute sodi roxi v i nh011 ha se a is extracted with ether and dried over anhydrous sodiumsulfate. The solvent is removed by distillation and the residueconverted into the hydrochloride, which after two recrystallizationsfrom acetone, melts at 156-158 C. (corn). This compound is3-dimethylamino-1,1-dinhenylbutane hydrochloride.

a e of 3. d m ylam t 1,..1 liphe ylr butyl ethyl sulfone-The basicsulfone hydrochloride obtained in Example 3A by condensing benzohydrylethyl sulfone with 3-dimethylamino- 2-propy1 chloride is converted intothe corresponding base by dissolving the salt in water, liberating thebasic sulfone with dilute sodium hydroxide solution, extracting saidsulfone with ether, and evaporating the ether extract to dryness. Tengrams of this sulfone is dissolved in 300 ml. of ethanol and theresulting solution is heated under reflux with approximately 200 g. ofRaney nickel catalyst for six hours. The metal is then removed and thefiltrate concentrated to dryness. The residue is covered with 30 ml. ofn-hexane and cooled. The gummy solid that does not dissolve is removedby filtration and the filtrate extracted with dilute hydrochloric acid.The extracts are made basic and the liberated oil is extracted withether. After the ether solution is dried with anhydrous sodium sulfate,the ether is removed by distillation and the residue distilled to give3.0 g. of colorless oil, B. P. 138-140 C. at 1 mm. This is dissolved inether and treated with ethanolic hydrogen chloride. A gum separateswhich solidifies on trituration with acetone. After tworecrystallizations from acetone the salt melts at 155-157 C. (corn) anddoes not depress the M. P. of the hydrochloride obtained by the cleavageof dimethylamino 2,2 diphenylbutanenitrile. Thus, this product also is3-dimethylamino-1,1- diphenylbutane hydrochloride.

EXAMPLE 4 3-diethyZamino-1,1-diphenylpropyl ethyl sulfonehydrochloride.-If the directions given in Example l-C are followed, butusing 22 g. of benzohydryl ethyl sulfone, 3.4 g. of sodium amide, 11.8g. of Z-diethylaminoethyl chloride, and ml. of dry toluene, there isobtained a gum which is taken up in alcoholic hydrogen chloride. Thehydrochloride of the base (about 10 g.) precipitates on cooling. Aftertwo recrystallizations from methanol-ether, about 8.0 g. of3-diethylamino-1,1-diphenylpropyl ethyl sulfone hydrochloride, M P.166.5-168 C. (corn), is obtained.

EXAMPLE 5 A. Q-flucrenethioL-A solution of 52 g. of 9- chlorofluoreneand 21.2 g. of thiourea in 150 ml. of ethanol is refluxed for two hours.Then 180 ml. of 10% sodium hydroxide solution is added and boiling iscontinued for ninety minutes. A solution of 14 ml. of sulfuric acid inml. of water is added to the mixture, and the solid I that separates oncooling is filtered and recrystallized twice from methanol containing asmall quantity of acetic acid. The resulting 9-fluorenethiol, whichseparates as shining white plates, melts at -106 C.

B. 9-fluorenyl ethyl sulfone.About 20 g. of 9-fluorenethiol is dissolvedin 100 ml. of ethanol containing 2.3 g. of sodium and 10.9 g. of ethylbromide, and the resulting solution is refluxed for two hours and thenpoured into water. The solid that separates (about 20 g.) is collectedand dissolved in 100 m1. of acetic acid. To the stirred acidic solutionmaintained at 80-90 C. is added dropwise 55 ml. of 30% hydrogenperoxide. Heating at 95 C. is continued for thirty minutes after all theperoxide has been added. The solution is poured into water, and theprecipitated solid is filtered and recrystallized from ethanol. About9.2 g. of 9-fluorenyl ethyl sulione, M. P. about 168 C., is obtained.This sulfone can be recrystallized from ethanol to afford ananalytically pure sample.

C. 9- (2- (1 -piperidyl) ethyl) -9-fluorenyl ethyl sulfonehydrochloride-A mixture of 9.2 g. of Q-fluorenyl ethyl sulfone, 4.2 g.of 2-(1-piperidyl)ethyl chloride, and 1.5 g. of sodium amide in 40 ml.of toluene is refluxed for five hours. After processing in the mannerdescribed above in Example l-C, there is obtained an oily sulfone whichis taken into ether. The ether solution is dried over anhydrous sodiumsulfate, the ether is removed by distillation, and the residue istreated with alcoholic hydrogen chloride to yield the hydrochloride of9-(2-(1-piperidyl) ethyD-Q-fluorenyl ethyl sulfone, which, afterrecrystallization from methanol-ether, melts at 194.8-196.8 C. (corn)EXAMPLE 6 1,1-diphenyZ-4-(I-piperidybbutyl ethyl sulfone.A mixture of24.6 g. of benzohydryl ethyl sulfone, 3.7 g. of sodamide, 15.4 g. of3-(1-piperidyDpropyl chloride, and 100 ml. of toluene is heated underreflux for three hours. Then ml. of ethanol is added to destroy anyexcess sodium amide, and the mixture is diluted with water. The toluenelayer is separated and extracted with dilute hydrochloric acid. Theacidic extract is made alkaline with dilute sodium hydroxide solution,whereupon there separates an oil which is taken up into ether. Afterdrying the ethereal extract over anhydrous sodium sulfate, the ether isremoved by distilling in vacuo, and the resulting residue is trituratedwith a small amount of ether and petroleum ether (n-pentane) untilcrystallization results. There is obtained 11.4 g. of crude product,which, after recrystallization from ethanol, melts at 112- 113.5 C.(corn). This product is 1,1-diphenyl- 4-(1-piperidy1) butyl ethylsulfone.

When 1,1-dipheny1-4-(l-piperidyl)butyl ethyl sulfone is treated withmethyl bromide, the corresponding methyl bromide quaternary derivativeis obtained. Similarly, using benzyl chloride instead of methyl bromide,the corresponding benzyl chloride quaternary derivative is formed.

EXAMPLE 7 A. Benzohydryl n-propyl sulfone.To an ethanolic solution ofsodium ethoxide (from 4.6 g. of sodium and 200 ml. of absolute ethanol)are added 40 g. of diphenylmethanethiol and 18.3

ml. (24.6 g.) of n-propyl bromide. After refluxing for three hours, theethanol is removed by distillation, the residual solution poured intowater, and the resulting mixture extracted with ether. The ether isremoved by distillation, the residue covered with toluene, and thelatter removed by distillation.

The resulting benzohydryl n-propyl sulfide is dissolved in '75 ml. ofacetic acid, and 60 ml. of 30% hydrogen peroxide solution is added drop-Wise with stirring over a period of about thirty minutes, while keepingthe temperature of the reaction mixture between 80-90 C. After thereaction mixture has been allowed to cool, it is poured into water. Theresulting precipitate is filtered, washed well with water, andrecrystallized from ethanol-water to yield about 38 g. of benzohydryln-propyl sulfone, M. P. 110-3 C.

B. 3-dimethg1Zamino-1,l-diphenylbatg l n-propyl sulfone bitartrate.-Amixture of 27.6 g. of benzohydryl n-propyl sulfone, 12.5 g. of2-dimethylamino-l-propyl chloride, 6.0 g. of sodium amide, and 100 ml.of dry toluene is heated to about 100 C. whereupon an exothermicreaction ensues, causing the temperature to rise about six degrees.After about fifteen minutes the exothermic reaction subsides, and thereaction mixture is refluxed for an additional five hours. Ethanol andwater are added to the cooled reaction mixture to decompose the excesssodium amide. The toluene layer is separated and extracted with dilutehydrochloric acid. The acidic layer is then extracted with ether andmade basic with dilute sodium hydroxide solution to yield a gum, whichis taken up in chloroform. After removal of the chloroform by vacuumdistillation, the residue is taken up in a solution of 10.0 g. oftartaric acid in 20 ml. of water. The resulting solution is placed in anicebox overnight. The precipitated salt is filtered, and recrystallizedonce from water and twice from ethanol-ether, giving3-dimethylamino-1,1-diphenylbutyl n-propyl sulfone bitartrate, M. P.148.2-151" C. (corr.).

EXAMPLE 8 A. Benzohydryl isopropyl suZfone.-This preparation is carriedout essentially like that shown in example 7A, but using 19.9 ml. ofisopropyl iodide in place of 18.3 ml. of n-propyl bromide and a refluxperiod of five hours instead of three. The benzohydryl isopropyl sulfideis oxidized according to the directions given in example 7A, and thereis thus obtined 35.8 g. of benzohydryl isopropyl sulfone, M. P. 190-2 C.

B. 3-dz'metlryl-L1-diphenylbutyl Z-pmpyl sulfone bitartrate.-Thispreparation is carried out like that described in Example 73, but usingbenzohydryl isopropyl sulfone in place of benzohydryl n-propyl sulfone.The resulting basic sulfone is 3-dimethylamino-1,1-diphenylbutyl 2-propyl sulfone bitartrate.

EXAMPLE 9 3dimethyZamino-1,1-diphenyl1oropyl ethyl sulfonehydrochloride-This preparation is carried out according to thedirections given in Example 4, but using 26 g. of benzohydryl ethylsulfone, 14.4 g. of 2-dimethylaminoethyl chloride hydrochloride, 10 g.of sodium amide, and ml. of dry toluene. After two recrystallizationsfrom ethyl acetate (plus a small quantity of absolute ethanol), theresulting product, 3-dimethylamino-1,1-diphenylpropyl ethyl sulfonehydrochloride melts at 2028-2043 C. (corn).

EXAMPLE 10 A. Beneohydryl cycZopentg Z sulfone-To a solution of ml. ofabsolute ethanol containing 4.6 g. of. sodium is added 40 g. ofdiphenylmethanethiol followed by 30 g. of cyclopentyl bromide. Thereaction mixture is heated with stirring for four hours and then pouredonto ice and water. The semi-solid material that separates is taken upin toluene, and the toluene removed by distilling in vacuo.

The residual benzohydryl cyclopentyl sulfide is dissolved in 120 m1. ofacetic acid, and 70 ml. of 30% hydrogen peroxide solution is addeddropwise with stirring over a period of about thirty minutes, whilekeeping the temperature of the reaction mixture between 60-75 C. Afteraddition of the hydrogen peroxide has been completed, the reactionmixture is heated at 8090 C. for an additional thirty minutes, and thenpoured onto ice and water. The solid that separates is filtered andrecrystallized onc from ethyl acetate-dioxane and once from dioxane togive the product, benzohydryl cyclopentyl sulfone, M. P. 193-4" C.

When the above procedure is followed but using cyclohexyl bromide inplace of cyclopentyl bromide, the product that results is benzohydrylcyclohexyl sulfone. I

B. 3 -dimethyZamino-1,1-diphenylbutyl cyclopentyl sulfone.-When theprocedure used in Example 6 is followed, but using 30 g. of benzohydrylcyclopentyl sulfone, 100 ml. of dry toluene, 10 g. of sodium amide, and16.2 g. of 2-dimethylamino-l-propyl chloride, there is obtained as theproduct 3-dimethylamino-1,l-diphenylbutyl cyclopentyl sulfone.

When benzohydryl cyclohexyl sulfone is used in place of benzohydrylcyclopentyl sulfone in the above procedure, there is obtained as theproduct 3-dimethylamino-1,1-diphenylbutyl cyclohexyl sulfone.

EXAMPLE 11 A. Benzohyd'ryl isobutyl suZfne.-This preparation is carriedout like that described in Example lOA, but using 27.4 g. of isobutylbromide in place of the cyclopentyl bromide. The resulting product,benzohydryl isobutyl sulfone, melts at 130-1 C. after beingrecrystallized from ethanol-water.

B. B-(Z-piperidyl)-1,1-diphenyZprom/Z isobutyl suZfone.--'I'hispreparation is carried out like that described in Example 10, but using28.8 g. of benzohydryl isobutyl sulfone, g. of sodium amide, 100 ml. ofdry toluene, and 18.4 g. of 2 (1 piperidyl)ethyl chloride hydrochloride.The resulting product is 3-(l-piperidyl) -1,1-diphenylpropyl isobutylsulfone.

EXAMPLE 12 3-(1-piperidyl) 1,1 diphenylbutyl ethyl suifone.16.4 g. ofZ-(I-piperidyl)-1-propy1 chloride is added dropwise to a stirred mixturecontaining 26 g. of ethyl benzohydryl sulfone, 100 ml. of toluene, and 6g. of sodium amide at 80 C. whereupon the temperature rises rapidly toabout 112 C. The resulting reaction mixture is then refluxed for threehours and cooled. After ethanol has been added to destroy the excesssodium amide, water is added, and the organic layer separated andextracted with 26% aqueous hydrochloric acid. The acidic extract is madealkaline with dilute sodium hydroxide solution and the liberated basicproduct is taken up in chloroform. Removal of the chloroform bydistilling in vacuo leaves a residue, which is covered with benzene,which in turn is removed by distilling in vacuo. Trituration of theresidue with ether results in the formation of a solid, which isfiltered, washed with ether and then n-pentane, and recrystallized frommethanol. The resultin product is probably 3-(1-piperidyl)-1,1-diphenylbutyl ethyl sulfone, M. P. 160-1616 C. (corn), of theformula The structure of this basic sulfone is assigned by analogy onthe basis of the structure proof of the isomeric3-dimethylamino-1,1-diphenylbutyl ethyl sulfone, as described in Example36.

We claim:

1. A member of the group consisting of a basic sulfone having theformula BXC(Ar) (Ar')SO2-R where B is a lower dialkylamino group inwhich the alkyl groups may be joined to form a heterocyclic radial ofthe group consisting of piperidines, morpholines and pyrrolidines, X isa lower alkylene group, Ar and Ar are aryl groups of the benzene series,and R is a lower hydrocarbon radical having l-8 carbon atoms, saidhydrocarbon radical being selected from the group consisting of alkyland cycloalkyl having 3-6 ringcarbon atoms, and acid-addition andquaternary ammonium salts thereof.

2. A basic sulfone having the formula where B is a lower dialkylaminoroup, X is a lower alkylene group, Ar and Ar are aryl groups of thebenzene series, and R is a lower alkyl group.

3. A basic sulfone having the formula where B is a lower dialkylarninogroup, X is a lower alkylene group, and Ar and Ar are aryl groups of thebenzene series.

4. A basic sulfone having the formula where B is a lower dialkylaminogroup, and Ar and Ar are aryl groups of the benzene series.

5. A basic sulfone having the formula BCH (Cm) CHzC (CsHs) (Col-I5)SO2C2H5 where B is a lower dialkylamino group.

6. A 3-dimethylamino-1,1-diphenylbutyl ethyl sulfone.

'7. Levo 3 dimethylamino-1,1 diphenylbutyl ethyl sulfone.

8. The process of preparing a basic sulfone having the formulaBX--halogen where B and X have the meanings designated hereinabove inthe presence of a basic condensing agent.

9. The process of preparing a basic sulfone having the formula where Bis a lower dialkylamino group, X is a lower alkylene group, Ar and Arare aryl groups of the benzene series, and R is a lower alkyl group,which comprises heating a sulfone having the formula, AICH(AI")SO2R,with an aminoalkyl halide having the formula,

BXhalogen,

where B and X have the meanings designated hereinabove in the presenceof sodium amide.

10. A basic sulfone having the formula where B is a l-piperidyl group, Xis a lower alkylene group, Ar and Ar are aryl groups of the benzeneseries. and R is lower alkyl.

17 11. A basic sulfone having the formula where B is a l-piperidylgroup, X is a lower alkylene group, and Ar and Ar are aryl groups of thebenzene series.

12. A basic sulfone having the formula where B is a l-piperidyl group,and Ar and Ar are aryl groups of the benzene series.

13. 3 (1 piperidyl) 1,1-diphenylbutyl ethyl sulfone.

14. 3-(1-piperidyl)-1,1diphenylpropyl methyl sulfone.

15. 3-dimethylamino-L1-diphenylpropyl ethyl sulfone.

16. The process of preparing a basic sulfone having the formula where Bis a lower dialkylamino group, X is a lower alkylene group, and Ar andAr are aryl groups of the benzene series, which comprises heating asulfone having the formula,

with an aminoalkyl halide having the formula, B-X-halogen, where B and Xhave the meanings designated hereinabove, in the presence of sodiumamide.

17. The process of preparing a basic sulfone having the formula where Bis a l-piperidyl group, X is a lower alkylene group, Ar and Ar are arylgroups of the benzene series, which comprises heating a sulfone havingthe formula, ArCH(Ar) SO2C2H5, r

with an aminoalkyl halide having the formula, BXhalogen, where B and Xhave the meanings designated hereinabove, in the presence of sodiumamide.

19. A basic sulfone having the formula B-XC Cal-I5) 2SO2R where B is alower dialkylamino group, X is a lower alkylene group and R is a loweralkyl group.

20. A basic sulfone having the formula where B is a l-piperidyl group, Xis a lower alkylene group and R is a lower alkyl group.

21. The process of preparing a basic compound having the formula where Bis a lower dialkylamino group, X is a lower alkylene group and R is alower alkyl group, which comprises heating a sulfone having the formula,(CeH5)2CH-SO2R, with an aminoalkyl halide having the formulaB--X--halogen where B, X and R have the meanings designated hereinabove,in the presence of a. basic condensing agent.

22. The process of preparing a basic compound having the formula where Bis a l-piperidyl group, X is a lower alkylene group and R is loweralkyl, which comprises heating a sulfone having the formula, (CeHs)2CH--SO2R, with an aminoalkyl halide having the formula, B-X-halogen,where B, X and R. have the meanings designated hereinabove, in thepresence of a basic condensing agent.

SYDNEY ARCHER.

CHESTER M. SUTER.

BENJAMIN F. TULLAR.

REFERENCES CITED The following references are of record in the file ofthis patent:

UNITED STATES PATENTS Number Name Date 2,140,608 Ufer Dec. 20, 19382,207,021 Martin et a1 July 9, 1940 OTHER REFERENCES Eisleb: Ber. derDeu. Chem, vol. 7413 (1941), p. 1438.

1. A MEMBER OF THE GROUP CONSISTING OF A BASIC SULFONE HAVING THEFORMULA